Public Release: 24-Jun-2008
Also in the June 24 JNCI

Identification of a Tumor Suppressor Gene Associated with Patient Outcome in Neuroblastoma

Expression of the CHD5 gene is frequently down-regulated in neuroblastomas, and patients whose tumors lacked CHD5 expression were more likely to have shorter event-free and overall survival compared with patients whose tumors expressed CHD5.

Neuroblastoma tumors often lack one copy of a region on the short arm of chromosome 1, called 1p36.31. Garrett Brodeur, M.D., of the Children's Hospital of Philadelphia and colleagues previously identified the smallest region spanned by the deletion in more than 1,200 patient tumors and found that 23 genes were located within the region.

In the current study, Brodeur and colleagues examined the expression pattern of CHD5 in neuroblastoma cell lines and the impact of replacing the missing copy of this gene in animal models. They also looked at the association between expression of each of the 23 genes from the region and clinical outcome in 99 patients.

Although the remaining copy of the CHD5 gene is rarely mutated in neuroblastomas, the authors found that the gene is epigenetically silenced in neuroblastoma cell lines with 1p deletion. Patients whose tumors showed high expression of CHD5 protein had approximately 7-fold longer event-free and overall survival than those patients whose tumor showed low CHD5 expression. Other genes in the region did not show a consistent association with neuroblastoma prognostic features and patient outcomes.

"These results demonstrate that CHD5 expression is strongly associated with outcome in neuroblastomas, CHD5 is the likely target of 1p deletions in these tumors, and it may have a direct role in the biology and behavior of neuroblastomas," the authors write.

Mice immunized with an intestinal protein developed fewer lung and liver metastases following injection with colon cancer cells than unvaccinated animals.

Researchers are hindered in the development of cancer vaccines by a lack of antigens that are specific for tumors and not expressed elsewhere in the body. Immunization with antigens that are expressed elsewhere in the body raises the possibility of autoimmune complications. However, the intestinal lining and some other mucosal areas are protected from the immune system and some proteins from these immune protected sites are widely expressed on tumor cells. Therefore such proteins may be safe and effective antigens for anti-cancer vaccines.

To test this possibility, Adam Snook, Ph.D., and Scott Waldman, M.D., Ph.D., of Thomas Jefferson University in Philadelphia and colleagues immunized mice with a viral vector that expressed guanylyl cyclase C protein, which is normally only expressed in the intestinal lining and is expressed by metastatic colorectal cancer cells. The researchers injected the animals with colon cancer cells before or after immunization with guanylyl cyclase C.

The vaccinated animals developed fewer metastases in the liver and lung compared with control animals. Vaccination also prolonged overall survival, with a median of 38 days in immunized animals and 29 days in control animals. The investigators did not see any evidence of autoimmune responses.

The researchers hypothesize that the approach of using antigens from immune-restricted sites might be extended to other cancers that originate from mucosa, including cancers of the head and neck, lung, breast, vagina, and bladder.

Multiple Regions of Chromosome 8 Found To Be Associated with Different Cancers

A recently discovered, but not yet understood, section of chromosome 8, called 8q24, may contain at least five distinct regions that are associated with different cancers.

Recent genome-wide studies suggested that genetic alterations in the 8q24 region are associated with a risk of prostate, colorectal and breast cancer. The region does not contain any known genes and is referred to as a gene desert, but researchers have mapped it using single nucleotide polymorphisms (SNPs) as markers.

To determine whether 8q24 acts as a single region associated with all of these cancers or if it could be sub-divided into smaller regions, Maya Ghoussaini, Ph.D., of the University of Cambridge and colleagues tested the associations of nine SNPs spaced along the region in four different sets of DNA, each comprising patients with one of the four cancers and healthy controls.

The authors' analysis suggests that there may be five distinct subregions within 8q24, separated by sites of frequent recombination, and each associated with different types of cancer. The first subregion is associated with an increased risk of prostate cancer but not with risk of breast, colorectal, or ovarian cancer. The second is associated only with an increased risk of breast cancer. The third subregion is associated with the risk of prostate, colorectal and ovarian cancers, but not breast, and subregions four and five were associated with prostate cancer, but not with the other three malignancies.

"We have shown there are at least five independent loci within this gene desert with different associations with particular cancers," the authors write. "Further studies of the region may identify additional loci associated with specific cancers and possibly refine our understanding of the mechanisms underlying the associations reported here."

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is not associated with a reduction in the risk of melanoma, according to the results of a large cohort study.

Laboratory studies have suggested that NSAID use may be associated with a reduction in the risk of melanoma, but few epidemiological studies have investigated the issue.

To determine if there is an association, Maryam Asgari, M.D., of the Kaiser Permanente Northern California in Oakland and colleagues compared NSAID use over ten years and the incidence of melanoma in 63,809 individuals. The cohort was drawn from the Vitamins and Lifestyle cohort study. Melanoma cases were identified using the Surveillance, Epidemiology, and End Results (SEER) database.

The researchers identified 349 new melanoma cases in the cohort during the follow-up period. After adjusting for known melanoma risk factors, no association with NSAID use and melanoma risk was found. "The lack of effect was persistent even though our NSAIDs variables accounted for frequency and duration of NSAID use and we considered the major classes of NSAIDs separately and combined," the authors write.

Established criteria for evaluating the impact of large epidemiologic cohort studies, often questioned on the basis of their cost, have been lacking. Graham Colditz, M.D., Dr.P.H., of Washington University School of Medicine in St. Louis and Deborah Winn, Ph.D., of the National Cancer Institute in Bethesda, Md., propose a set of criteria that follow the discovery, development, and delivery paradigm used by the National Institutes of Health. They applied these criteria to the Nurse's Health Study (NHS).

To evaluate the NHS, in terms of discovery, the researchers used the number of journal articles produced from the cohort study and the impact factor of the journals in which those articles were published. To measure the contribution of the study to development, the authors assessed the degree to which it provided scientific support for prevention and clinical trials and clinical guidelines and the extent to which its findings contributed to risk models. In the area of delivery, the researchers proposed that metrics sensitive to a study's effect on public awareness and its industry and policy applications were needed.

Colditz and Winn found that the NHS has been valuable and productive. For example, NHS researchers have published 36 publications in the New England Journal of Medicine, 41 in the Journal of the American Medical Association, and 41 in the Journal of the National Cancer Institute. Data from this study and several other epidemiologic studies led to the American Cancer Society's recommendation that individuals reduce their intake of alcohol and red meat and increase their physical activity. NHS data has also led to chemoprevention trials.

"Our analysis of the NHS reveals that this cohort has been success¬ful in terms of discovery, development, and delivery. Moreover, we suggest that the approach to assessment that we outline can be used to evaluate other cohorts and other epidemiological studies," the authors write.

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